1. Technical Field
This invention relates to opioids, and in particular co-administration of sub-analgesic doses of a .mu.-opioid agonist and a .kappa..sub.2 -opioid agonist for the production of analgesic synergy.
2. Background Art
Opioid analgesics such as morphine, hydromorphone, oxycodone and fentanyl are among the most powerfully acting and clinically useful drugs producing depression of the central nervous system. These analgesics are the mainstay for the treatment of moderate to severe cancer pain because they are simple to administer and they provide effective pain relief in most patients when used properly (Cancer Pain Relief, World Health Organization, 1986, Geneva).
Unlike doses of non-opioid drugs, weak opioids and mixed opioid agonist-antagonists (e.g., buprenorphine), the doses of morphine and other strong opioids can be increased indefinitely, being limited only by the development of unacceptable side effects. These side effects include the development of physical dependence and tolerance, sedation, respiratory depression, hypotension, increase in cerebrospinal fluid pressure, nausea, vomiting and constipation.
In some patients, particularly the chronically ill, the opioid side effects make it impossible to administer dosages sufficient to adequately control pain over the required time period. Therefore, more active analgesic combinations are in constant demand which offer the possibility of relieving pain with reduced dosages to thereby diminish the expected side effects and toxicity that might result from the otherwise required higher dosages.
In order to explain the above dichotomous effects, it has been postulated (U.S. Pat. No. 5,512,578) that strong opioids such as morphine are bimodally-acting in that they activate both inhibitory and excitatory opioid receptor-mediated functions of neurones in the nociceptive pathways of the nervous system. In this regard, the inhibitory receptors are considered to be responsible for the production of analgesia and the excitatory receptors are regarded to be involved in the production of some of the undesirable side effects referred to above.
Morphine remains the most widely used analgesic for treatment of moderate to severe pain and is the gold standard against which all opioids are compared. In an effort to make morphine of greater use in the treatment of pain, it has been combined with a variety of substances intended to inhibit one or more of its undesirable side effects. To this end, reference may be made to U.S. Pat. No. 2,770,569 which is directed to a combination of morphine with the compound levo-d-hydroxy-N-allyl-morphinan which is said to suppress or eliminate such undesirable side reactions of morphine as respiratory depression, nausea and vomiting.
Reference also may be made to U.S. Pat. No. 4,126,684 which discloses a reduction of either the addiction liability of an addictive substance such as a narcotic analgesic or a barbiturate or the withdrawal symptoms caused by deprivation of such a substance in an addicted subject by administering the addictive substance, e.g., morphine with a 4-amino-3-p-halophenylbutyric acid. In U.S. Pat. No. 4,415,871, reference is made to the prevention of treatment tolerance and physical dependence in chronic morphine treatment by combining the morphine with any of the specific dipeptides indicated therein.
In U.S. Pat. No. 5,041,446 there is disclosed a method of inhibiting the development of tolerance to morphine by combining the morphine with dapiprazole.
In U.S. Pat. No. 5,057,519 there is described a reduction in morphine tolerance by combining the morphine with a benzamide antagonist for a sub-type of the serotonin receptor, 5-HT.sub.3.
Reference also may be made to U.S. Pat. No. 5,321,019 in which is disclosed a composition containing an addictive substance such as morphine or codeine and at least one non-toxic substance that blocks the N-methyl-D-aspartate (NMDA) receptor which inhibits the development of tolerance to and/or dependence on the addictive substance.
In addition to morphine, other strong opioids have been combined with a variety of substances intended to alleviate one or more of their undesirable side effects. To this end, reference may be made to U.S. Pat. No. 4.569,937 which is directed to pharmaceutical compositions of ibuprofen and narcotic analgesics such as oxycodone, oxymorphone, hydrocodone, hydromorphone, morphine, meperidine, and methadone. These compositions were found to exhibit unexpected synergism enabling the use of lower doses of either or both drugs with a concomitant reduction in risk of possible side effects.
Reference also may be made to U.S. Pat. No. 4,769,372 which describes a method for treating chronic pain or chronic cough in a patient while preventing or alleviating the development of constipation or other symptoms of intestinal hypomotility wherein an opioid analgesic or antitussive such as morphine, meperidine, oxycodone, hydromorphone, codeine and hydrocodone is administered to the patient together with an opioid antagonist such as naloxone, naloxone glucuronide and nalmefene glucuronide. However successful this therapeutic combination may be in inhibiting the development of constipation or other symptoms of intestinal hypomotility, it does not address the problems of tolerance and/or dependence that are associated with the long term administration of narcotic analgesics.
In Australian Patent Application 88042/82 reference is made to an analgesic composition comprising an analgesic effective amount of a narcotic analgesic selected from the group consisting of morphine, oxymorphone, oxycodone and hydromorphone and an analgesic effective amount of nalbuphine. These combinations are said to improve analgesia while reducing or eliminating the respiratory depression and euphoria usually associated with narcotics.
Reference also may be made to European Patent Application Publication No. 0080047 which discloses combinations of a strong opioid such as morphine or oxycodone with the carbazole compound 6-chloro-.alpha.-methyl-carbazole-2-acetic acid. This carbazole compound is said to potentiate the analgesic action of morphine or oxycodone, thereby reducing the amount of opioid used.
In U.S. Pat. No. 5,317,022 there is disclosed a composition for the selective blockade of opioid binding sites of the brain responsible for respiratory depression comprising an analgesic effective amount of a codeine derivative and in a mass ratio of 1:2-3 morphine or a morphine derivative indicated therein.
Reference also may be made to U.S. Pat. No. 5,512,578 which is directed to a method for selectively enhancing the analgesic potency (inhibitory effects) of a bimodally-acting opioid agonist such as morphine and simultaneously attenuating the undesirable side effects (excitatory effects) caused by chronic administration thereof comprising co-administration of the bimodally-acting opioid agonist and an opioid receptor antagonist which selectively inactivates excitatory opioid receptor-mediated side effects. Accordingly, this mode of analgesia is purported to be effected by co-administration of two opioid compounds, one of which binds to and acts as a selective agonist at inhibitory opioid receptors to cause analgesia and the other of which binds to and acts as a selective antagonist at excitatory opioid receptors so as to attenuate undesirable side effects caused by the administration of the bimodally-acting opioid agonist while simultaneously enhancing the analgesic effects thereof. In particular, the studies disclosed in U.S. Pat. No. 5,512,578 showed that in cultured fetal dorsal root ganglion sensory neurones co administration of conventional concentrations (.mu.M) of bimodally-acting opioid agonists such as morphine with ultra-low concentrations (fM-pM) of opioid receptor antagonists such as naloxone, naltrexone, diprenorphine, etorphine and dihydroetorphine resulted in a marked shortening of the action potential duration (APD) which is consistent with markedly enhanced inhibitory effects.
It is a commonly held view (Mather, L. E., 1995, Clin. Exp. Pharmacol. Physiol., 22, 833-836) that all clinically used opioid drugs including hydromorphone, oxycodone and fentanyl mediate their analgesic/antinociceptive effects in the same manner as morphine; i.e., by interacting with .mu.-opioid receptors in the CNS To this extent, recent years have seen the development of novel opioid analgesics acting through receptors distinct from those utilized by morphine. Three major types of opioid receptors have been pharmacologically defined, namely .mu., .delta., and .kappa., and these are further subdivided into various subtypes (for a review see Pastemak, G. W., 1993, Pharmacological Mechanisms of Opioid Analgesics In Clin. Neuropharmacol., 16, 1-18). It has been suggested that since the effects of endogenous opioids are mediated by at least these three different receptor types, highly selective exogenous opioid agonist or antagonist ligands might have therapeutic applications (Martin, W. R., 1983, Pharmacol. Rev., 35, 283). Thus, if a ligand acts at a single opioid receptor type or sub-type, the potential side effects mediated through other opioid receptor types can potentially be minimised or eliminated.
In this regard, reference may be made to U.S. Pat. No. 5,352,680 which is directed to a therapeutic method for treating opioid tolerance comprising administering a .delta.-opioid receptor antagonist to block or reduce the tolerance of an opioid .mu.-receptor agonist such as morphine.
Reference also may be made to U.S. Pat. No. 5,319,087 which discloses the blocking of the .mu. or .kappa. receptors in the brain using trans-3,4-1-substituted-3-substituted-4-methyl-4-(3-substituted phenyl)-piperidines as opioid antagonists.
Several studies have demonstrated that combinations of .mu.- and .delta.-agonists, administered intrathecally, produce enhanced analgesic effects or analgesic synergy (i.e., more than additive analgesic effects) (Larson et al., 1980, Eur. J. Pharmacol., 61, 381-383; Roerig & Fugimoto, 1989, J. Pharmacol. Exp. Ther. 249, 762-768). Other studies have shown that simultaneous intrathecal administration of combinations of a selective .mu.-opioid agonist (DAMGO) with both a .kappa..sub.1 -selective (U50,488H) or a .delta.-selective (DPDPE) opioid agonist also produce analgesic synergy (Miaskowski et al., 1990, Brain Research, 509, 165-168) in addition, potent analgesic synergy has been observed with combinations of a low-analgesic dose of a selective .mu.-agonist (DAMGO) co-administered into the central nervous system (CNS) with sequentially increasing doses of either a selective .delta.-(DPDPE) or a selective .kappa..sub.1 -agonist (U50,488H) (Sutters et al., 1990, Brain Research, 530, 290-294).
These studies demonstrate that all three major classes of opioid receptors can interact to produce antinociceptive synergy. However, the magnitude of the interactions vary markedly depending on which combinations of selective opioid receptor agonists are administered. The data from these studies demonstrate that co-activation of the .mu.-opioid receptor, with either .delta.- or .kappa..sub.1 -opioid receptors, results in the largest enhancement in antinociceptive effects. Importantly, these marked enhancements in antinociception are not attributable to increases in motor deficits.
From the foregoing, a number of non-toxic substances have been defined which may ameliorate some of the undesirable side effects resulting from prolonged administration of strong opioids. In addition, combinations of experimental substances have been defined including .mu.-, .kappa..sub.1 - and .delta.-agonists which result in a synergistic increase in analgesia.
None of these references, however, suggest in any way the desirability of concurrent administration of two strong opioids for analgesic synergy and/or amelioration of their respective undesirable side effects. In fact, just the opposite is suggested. For example, in the World Health Organization's (WHO) guidelines for the relief of cancer pain (Cancer Pain Relief, 1986, supra), it is recommended that co-administration of two strong opicids should never be attempted. Instead, it is recommended that an analgesic ladder should be followed wherein a non-opioid drug is administered initially to a patient and when pain persists or increases, a weak opioid is added to the medication. When the weak opioid drug in combination with the non-opioid drug fails to relieve the pain, a strong opioid is then administered in place of the weak opioid drug. Importantly, it is stipulated that only one opioid drug should be given at any one time.
The current invention arises from the unexpected discovery that co-administration of sub-analgesic dosages of two strong opioids such as morphine and oxycodone results in potent analgesic synergy and a reduced propensity for causing the undesirable side effects herein described. It was further found that oxycodone is a .kappa..sub.2 -opioid agonist and that co-administration of a sub-analgesic dosage of a .kappa..sub.2 -opioid agonist with a sub-analgesic dosage of a .mu.-opioid agonist also results in strong analgesic synergy with reduced undesirable side effects.